scholarly journals When form meets function: the cells and signals that shape the lymphatic vasculature during development

Development ◽  
2021 ◽  
Vol 148 (11) ◽  
Author(s):  
Mathias Francois ◽  
Anna Oszmiana ◽  
Natasha L. Harvey
Keyword(s):  
Network Formation ◽  
Immune Cell ◽  
Lymphatic Endothelial Cell ◽  
Dietary Lipids ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Cellular Events ◽  
Formation Function ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

ABSTRACT The lymphatic vasculature is an integral component of the cardiovascular system. It is essential to maintain tissue fluid homeostasis, direct immune cell trafficking and absorb dietary lipids from the digestive tract. Major advances in our understanding of the genetic and cellular events important for constructing the lymphatic vasculature during development have recently been made. These include the identification of novel sources of lymphatic endothelial progenitor cells, the recognition of lymphatic endothelial cell specialisation and heterogeneity, and discovery of novel genes and signalling pathways underpinning developmental lymphangiogenesis. Here, we review these advances and discuss how they inform our understanding of lymphatic network formation, function and dysfunction.

scholarly journals Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0249256
Author(s):  
Esther Redder ◽  
Nils Kirschnick ◽  
Stefanie Bobe ◽  
René Hägerling ◽  
Nils Rouven Hansmeier ◽  
...  
Keyword(s):  
Laser Scanning ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Regulatory Elements ◽  
Dietary Lipids ◽  
Epifluorescence Microscopy ◽  
Lymph Vessel ◽  
Confocal Laser ◽  
Cell Trafficking ◽  
Tissue Fluid

Lymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements. We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery, liver and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

scholarly journals Hypercholesterolemia and Lymphatic Defects: The Chicken or the Egg?

2021 ◽  
Vol 8 ◽  
Author(s):  
Takuro Miyazaki ◽  
Akira Miyazaki
Keyword(s):  
Causal Relationship ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Invasion ◽  
Dietary Lipids ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Lipoprotein Composition ◽  
Factor C

Lymphatic vessels are necessary for maintaining tissue fluid balance, trafficking of immune cells, and transport of dietary lipids. Growing evidence suggest that lymphatic functions are limited under hypercholesterolemic conditions, which is closely related to atherosclerotic development involving the coronary and other large arteries. Indeed, ablation of lymphatic systems by Chy-mutation as well as depletion of lymphangiogenic factors, including vascular endothelial growth factor-C and -D, in mice perturbs lipoprotein composition to augment hypercholesterolemia. Several investigations have reported that periarterial microlymphatics were attracted by atheroma-derived lymphangiogenic factors, which facilitated lymphatic invasion into the intima of atherosclerotic lesions, thereby modifying immune cell trafficking. In contrast to the lipomodulatory and immunomodulatory roles of the lymphatic systems, the critical drivers of lymphangiogenesis and the details of lymphatic insults under hypercholesterolemic conditions have not been fully elucidated. Interestingly, cholesterol-lowering trials enable hypercholesterolemic prevention of lymphatic drainage in mice; however, a causal relationship between hypercholesterolemia and lymphatic defects remains elusive. In this review, the contribution of aberrant lymphangiogenesis and lymphatic cholesterol transport to hypercholesterolemic atherosclerosis was highlighted. The causal relationship between hypercholesterolemia and lymphatic insults as well as the current achievements in the field were discussed.

scholarly journals Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

2019 ◽  
Vol 8 (4) ◽  
pp. 495 ◽  
Author(s):  
Csányi ◽  
Singla
Keyword(s):  
Reverse Cholesterol Transport ◽  
Immune Cell ◽  
Imaging Techniques ◽  
Dietary Lipids ◽  
Cholesterol Transport ◽  
Cell Trafficking ◽  
Tissue Fluid ◽  
Lymphatic Function ◽  
Cardiovascular Tissue ◽  
Lymphatic Circulation

The lymphatic network is well known for its role in the maintenance of tissue fluid homeostasis, absorption of dietary lipids, trafficking of immune cells, and adaptive immunity. Aberrant lymphatic function has been linked to lymphedema and immune disorders for a long time. Discovery of lymphatic cell markers, novel insights into developmental and postnatal lymphangiogenesis, development of genetic mouse models, and the introduction of new imaging techniques have improved our understanding of lymphatic function in both health and disease, especially in the last decade. Previous studies linked the lymphatic vasculature to atherosclerosis through regulation of immune responses, reverse cholesterol transport, and inflammation. Despite extensive research, many aspects of the lymphatic circulation in atherosclerosis are still unknown and future studies are required to confirm that arterial lymphangiogenesis truly represents a therapeutic target in patients with cardiovascular disease. In this review article, we provide an overview of factors and mechanisms that regulate lymphangiogenesis, summarize recent findings on the role of lymphatics in macrophage reverse cholesterol transport, immune cell trafficking and pathogenesis of atherosclerosis, and present an overview of pharmacological and genetic strategies to modulate lymphatic vessel density in cardiovascular tissue.

scholarly journals Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

2021 ◽  
Author(s):  
Esther Redder ◽  
Nils Kirschnick ◽  
René Hägerling ◽  
Nils Hansmeier ◽  
Friedemann Kiefer
Keyword(s):  
Laser Scanning ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Regulatory Elements ◽  
Dietary Lipids ◽  
Epifluorescence Microscopy ◽  
Lymph Vessel ◽  
Confocal Laser ◽  
Cell Trafficking ◽  
Tissue Fluid

AbstractLymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements.We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

scholarly journals Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2340-2348 ◽  
Author(s):  
Ying Yang ◽  
José Manuel García-Verdugo ◽  
Mario Soriano-Navarro ◽  
R. Sathish Srinivasan ◽  
Joshua P. Scallan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Fluid Balance ◽  
Tissue Fluid ◽  
Lymphatic Endothelial Cells ◽  
Cardinal Vein ◽  
Cellular Processes ◽  
Mammalian Embryos ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

Abstract The lymphatic vasculature preserves tissue fluid balance by absorbing fluid and macromolecules and transporting them to the blood vessels for circulation. The stepwise process leading to the formation of the mammalian lymphatic vasculature starts by the expression of the gene Prox1 in a subpopulation of blood endothelial cells (BECs) on the cardinal vein (CV) at approximately E9.5. These Prox1-expressing lymphatic endothelial cells (LECs) will exit the CV to form lymph sacs, primitive structures from which the entire lymphatic network is derived. Until now, no conclusive information was available regarding the cellular processes by which these LEC progenitors exit the CV without compromising the vein's integrity. We determined that LECs leave the CV by an active budding mechanism. During this process, LEC progenitors are interconnected by VE-cadherin–expressing junctions. Surprisingly, we also found that Prox1-expressing LEC progenitors were present not only in the CV but also in the intersomitic vessels (ISVs). Furthermore, as LEC progenitors bud from the CV and ISVs into the surrounding mesenchyme, they begin expressing the lymphatic marker podoplanin, migrate away from the CV, and form the lymph sacs. Analyzing this process in Prox1-null embryos revealed that Prox1 activity is necessary for LEC progenitors to exit the CV.

scholarly journals Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity

2017 ◽  
Vol 313 (3) ◽  
pp. E303-E313 ◽  
Author(s):  
Rachel J. Roth Flach ◽  
Marina T. DiStefano ◽  
Laura V. Danai ◽  
Ozlem Senol-Cosar ◽  
Joseph C. Yawe ◽  
...  
Keyword(s):  
Immune Cell ◽  
Vascular Dysfunction ◽  
Chylous Ascites ◽  
Mitogen Activated Protein Kinase ◽  
Cell Trafficking ◽  
Metabolic Dysfunction ◽  
Vascular Integrity ◽  
Adult Mice ◽  
Mitogen Activated Protein ◽  
Lymphatic Vasculature

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium postdevelopment. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity.

Non-Invasive Assessment of Lymphatic Pumping Pressure in a Rat Tail Model Utilizing Near-Infrared Imaging

2013 ◽  
Author(s):  
J. Brandon Dixon ◽  
Ryan Akin ◽  
Mike Weiler ◽  
Timothy Kassis
Keyword(s):  
Near Infrared ◽  
Infrared Imaging ◽  
Immune Cell ◽  
Vessel Diameter ◽  
Lipid Absorption ◽  
Cell Trafficking ◽  
Non Invasive ◽  
Venous Circulation ◽  
Lymphatic Vasculature ◽  
Rat Tail Model

The lymphatic vasculature consists of a network of vessels that promote unidirectional transport of fluid, proteins, and cells from the interstitium back into the blood, providing functions essential for maintaining fluid balance, immune cell trafficking, and lipid absorption from the intestine. The lymphatics generate flow through both extrinsic pumping mechanisms, such as contraction of surrounding skeletal muscle, and through the intrinsic contractility of each lymphatic vessel unit known as a lymphangion. Specialized lymphatic muscle, working in coordination with uni-directional valves separating each lymphangion, serves to contract up to 80% of the vessel diameter and drive flow from the interstitium back to the venous circulation.

Characterization of Near-Infrared Functional Lymphatic Imaging in the Rat Tail Model

2013 ◽  
Author(s):  
Michael Weiler ◽  
J. Brandon Dixon
Keyword(s):  
Near Infrared ◽  
Immune Cell ◽  
Imaging Modality ◽  
Lymphatic Vessels ◽  
The Body ◽  
Cell Trafficking ◽  
Nir Imaging ◽  
Lymphatic Vasculature ◽  
Rat Tail Model ◽  
Lymphatic Imaging

The lymphatic vasculature is present in nearly every tissue of the body to serve essential functions in fluid homeostasis, immune cell trafficking, and lipid transport, and it has been implicated in the progression of several diseases. Despite the critical roles that this system performs, very little is known about the lymphatic vasculature in comparison to the blood vasculature, which can be attributed, in part, to the difficulty associated with imaging lymphatic vessels. With the growing interest in studying lymphatics, near-infrared (NIR) imaging has emerged in the literature as a novel lymphatic imaging modality to simultaneously improve spatial resolution to visualize small initial lymphatics and increase temporal resolution to capture the dynamic lymphatic pump function responsible for fluid propulsion.

scholarly journals Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1344
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Veronique Angeli
Keyword(s):  
Immune Cell ◽  
Lymphatic Vessels ◽  
Cardiovascular Complications ◽  
Chronic Inflammatory Disease ◽  
Cell Trafficking ◽  
Functional Roles ◽  
New Findings ◽  
Lymphatic Vasculature ◽  
Acute And Chronic Inflammation ◽  
Progression Of Atherosclerosis

In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.

scholarly journals Lymphatic Endothelial Cell Plasticity in Development and Disease

Physiology ◽  
2017 ◽  
Vol 32 (6) ◽  
pp. 444-452 ◽  
Author(s):  
Wanshu Ma ◽  
Guillermo Oliver
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Lymphatic Endothelial Cell ◽  
Lipid Absorption ◽  
Tissue Fluid ◽  
Mammalian Embryo ◽  
Fate Specification ◽  
Lymphatic Vasculature ◽  
Functional Features

The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.

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